Prospero homeobox 1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis

Abstract

Background Prospero homeobox 1 (PROX1) functions as a tumor suppressor gene or an oncogene in various cancer types. However, the distinct function of PROX1 in gastric cancer is unclear. We determined whether PROX1 affected the oncogenic behavior of gastric cancer cells and investigated its prognostic value in patients with gastric cancer. Methods A small interfering RNA against PROX1 was used to silence PROX1 expression in gastric cancer cell lines AGS and SNU638. Expression of PROX1 in gastric cancer tissues was investigated by performing immunohistochemistry. Apoptosis, proliferation, angiogenesis, and lymphangiogenesis were determined by performing the TUNEL assay and immunohistochemical staining for Ki-67, CD34, and D2-40. Results PROX1 knockdown induced apoptosis by activating cleaved caspase-3, caspase-7, caspase-9, and poly(ADP-ribose) polymerase, and by decreasing the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL. PROX1 knockdown also suppressed tumor cell proliferation. In addition, PROX1 knockdown decreased lymphatic endothelial cell invasion and tube formation and the expression of vascular endothelial growth factor (VEGF)-C and -D and cyclooxygenase (COX)-2. However, PROX1 knockdown only decreased umbilical vein endothelial cell invasion, not tube formation. The mean Ki-67 labeling index and lymphatic vessel density value of PROX1-positive tumors were significantly higher than those of PROX1-negative tumors. However, no significant difference was observed between PROX1 expression and apoptotic index or microvessel density. PROX1 expression was significantly associated with age, cell differentiation, lymph node metastasis, cancer stage, and poor survival. Conclusions These results indicate that PROX1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis.

Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer

“…It has been proposed that PROX1 is essential for lymphatic vascular system development by regulating endothelial cell differentiation and metastatic dissemination (31,32). Interestingly, qRT-PCR and Western blot analyses showed that PROX1 expression was significantly increased in exosomal LNMAT2-treated HLECs as compared with the control-treated HLECs (Figure 8, A and B, and Supplemental Figure 8, E and F), indicating that exosomal LNMAT2 upregulated PROX1 expression in HLECs.…”

Hallmarks of Cancer-Related Newly Prognostic Factors of Oral Squamous Cell Carcinoma

“…Reportedly, PROX1 plays various tumor-dependent functional roles, which reflect both the oncogenic potential and a tumor-suppressive role [90]. In addition, PROX1 promoted cell growth, angiogenesis, and sorafenib resistance in patients with HCC [102,91] and is associated with the lymphangiogenesis, metastasis, and poor prognosis in various malignancies [92,103,104]. However, high PROX1 expression is related to better prognosis for pancreatic and gastric cancer patients [105,106].…”

Disodium Cromolyn and Anti-podoplanin Antibodies Strongly Inhibit Growth of BHK 21/C13-derived Fibrosarcoma in a Chick Embryo Chorioallantoic Membrane Model

“…In a zebrafish model, it seems that PROX1 has a dual role in renal development: after its initial roles in the specification of inter-renal primordium, it is critical for the maturation of the inter-renal organ (33). Malignant transformation is followed by up-regulation of PROX1 in tumor cells reported for several types of cancer, such as gastric (34,35), pancreatic (36), vascular (37) and renal (38) cancer. For all these cancer types, PROX1 overexpression is related to high aggressiveness and poor prognosis (35).…”

“…Malignant transformation is followed by up-regulation of PROX1 in tumor cells reported for several types of cancer, such as gastric (34,35), pancreatic (36), vascular (37) and renal (38) cancer. For all these cancer types, PROX1 overexpression is related to high aggressiveness and poor prognosis (35). PROX1 distribution and expression in BHK-21/C13 fibrosarcoma may be considered a promoter of aggressive behavior of these cells, clinically detected during the development of the tumor in both hamster and the chick embryo CAM model.…”